Patients suffering from persistent knee joint pain typically have cartilage degeneration with structural and morphological changes in synovium, meniscus and subchondral bone at the damage knee joint region. Osteoarthritis is a leading cause of musculoskeletal-associated pain, psychological distress, impaired quality of life, and staggering socio-economic costs (estimated at $100 billion per year in the US alone). Currently, there is no effective treatment for this common affliction. Relief of knee joint pain is hampered because causative mechanisms (e.g., the pain source and affected cellular pathways) have not yet been established. To investigate the etiology of back pain and assess opportunities for possible clinical intervention, we will investigate specific signaling pathways leading to knee joit osteoarthritis and its symptom, knee pain by using representative tools: 1) established OA animal model model for facilitating behavioral pain assessments that allow us to investigate pain mechanisms, 2) genetically modified mice to understand pathophysiological nociceptive pathway evoked by knee osteoarthritis, and 3) investigation of peripheral (dorsal root ganglions) and central (spinal dorsal horn) responses by knee joint OA and roles of glial activation in chronic knee joint osteoarthritic pain. Our studies may uncover the nociceptive pathway that is impaired in OA condition, and may reveal that alleviation of OA pain at the spinal level is indeed beneficial to the joints by arresting progressive cartilage destruction through neurogenic attenuation. Successful completion of these studies will establish that effective controls of the PKC axis not only protects peripheral knee joint tissues from further degeneration, but also relieves its clinically debilitating symptom, pain, that profoundly impacts on the quality of life or a vast number of patients. PUBLIC HEALTH RELEVANCE: This application provides a unique opportunity to study nociceptive pathway initiated by osteoarthritis by combining genetically modified mice and established translational animal models that are amenable to behavioral pain tests that have set the stage for rapid advances in this highly under-studied area. Our results will discover a novel nociceptive pathway and molecular mechanisms that cannot be addressed by clinical protocols in humans, and will establish new experimental avenues and novel research directions for osteoarthritis-caused knee joint pain.